Biomedical Engineering Reference
In-Depth Information
10.3 Mechanisms of Action of ATRA and
Arsenic Trioxide
10.3.1 Mechanisms of ATRA Action
In 1985, a 5-year-old girl with APL in Shanghai became the first
patient to be treated with ATRA, a natural ligand of the retinoic acid
receptors, and obtained a durable complete remission [59]. The
presence of PML/RARα in the leukaemic cells is responsible for both
the disease pathogenesis and the remarkable sensitivity of the blast
cells to the therapy with ATRA. At the level of cellular morphology,
ATRA confers a striking change in the phenotype of APL cells that
shift from being immature promyelocytes to becoming short-lived
granulocytes. The differentiation effect has been described both
in
vivo
[15].
PML/RARα, in the context of being a mutated RARα, requires
high (10
and
in vitro
-7
-6
M) doses of ATRA in order to be transactivated
[47, 59]. This pharmacological concentration of ATRA causes a
conformational change of the chimera, just as the physiological
concentration does to the normal RARα. ATRA binds the fusion
protein through the ligand-binding domain of the RARα portion.
As a result, the co-repressor complex dissociates from the chimera
and co-activators, HATs and HMTs are recruited leading to the de-
repression of the RA-signalling target genes through the opening
of the chromatin structure. Accordingly, genome-wide epigenetic
studies revealed that treatment with pharmacological doses of ATRA
induces increase in H3 acetylation at the PML/RARα-RXR binding
sites or at nearby target genes, although, little or no changes to the
levels of H3K27me3, H3K9me3, or DNA methylation [41].
It was first thought that the profound curative effect originated
from ATRA's ability to reverse transcriptional repression of genes
responsible for myeloid differentiation. However, ATRA induces a
proteasome- and caspase-mediated degradation of the oncogene
as an additional effect. A kinetics analysis shows that ATRA causes
a biphasic PML/RARα degradation. A rapid decrease in PML/
RARα expression is observed already within 1 h, whereas a second
degradative step occurs after 12 h and is characterised by the
appearance of an 85-kDa PML/RARα cleavage product (
-10
∆
PML/
RARα). Not surprisingly, the ligand-binding domain required
